2xc3
From Proteopedia
X-ray structure of Mycobacterium tuberculosis cyp125 bound to the reverse type I inhibitor
Structural highlights
Function[CP125_MYCTU] Catalyzes the C-27 hydroxylation of cholest-4-en-3-one and cholesterol and subsequently oxidizes the alcohol of the former to the cholest-4-en-3-one-27-oic acid via the aldehyde intermediate. Not required to incorporate the cholesterol side-chain carbon atoms into cellular lipids.[1] [2] Publication Abstract from PubMedCytochrome P450 CYP125A1 of Mycobacteriumtuberculosis, a potential therapeutic target for tuberculosis in humans, initiates degradation of the aliphatic chain of host cholesterol and is essential for establishing M. tuberculosis infection in a mouse model of disease. We explored the interactions of CYP125A1 with a reverse type I inhibitor by X-ray structure analysis and UV-vis spectroscopy. Compound LP10 (alpha-[(4-methylcyclohexyl)carbonyl amino]-N-4-pyridinyl-1H-indole-3-propanamide), previously identified as a potent type II inhibitor of Trypanosomacruzi CYP51, shifts CYP125A1 to a water-coordinated low-spin state upon binding with low micromolar affinity. When LP10 is present in the active site, the crystal structure and spectral characteristics both demonstrate changes in lipophilic and electronic properties favoring coordination of the iron axial water ligand. These results provide an insight into the structural requirements for developing selective CYP125A1 inhibitors. Reverse type I inhibitor of Mycobacteriumtuberculosis CYP125A1.,Ouellet H, Kells PM, Ortiz de Montellano PR, Podust LM Bioorg Med Chem Lett. 2011 Jan 1;21(1):332-7. Epub 2010 Nov 5. PMID:21109436[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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